The present invention relates to compositions and methods for diagnosing and treating cancer. More particularly, the present invention relates to the use of MCP-1 inhibitors in treating prostate cancer and to methods of diagnosing prostate cancer via detection of MCP-1 expression or activity.
Cancer of the prostate (CaP) is the most common cancer in American males, and the second cause of cancer-related mortality22,23. Adenocarcinoma of the prostate attacks mainly men older than 50 years, and the high mortality rate is principally due to the spread of malignant cells to different tissues, a process called metastasis. Incidence and death rates from metastatic processes continue to grow substantially since 1980, with the aging population, hence the importance of early detection and treatment of the disease. The precise etiology of prostate cancer is unknown, although there is some hormonal relationship and possibly a multi-step process involved in the transformation of a benign epithelial cell to adenocarcinoma.
Chemokines are a group of small (˜8-14 kDa), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of seven-transmembrane, G protein-coupled receptors1.
The present inventor have previously shown that the immune system can selectively generate autoimmunity to chemokines and other proinflammatory mediators when such a response is beneficial for the host2-9. For example, patients suffering from rheumatoid arthritis (RA) but not osteoarthritis (OA) have significant levels of autoantibodies directed to TNF-α, and therapies that neutralize the function of TNF-α suppress RA but not OA2. Selective amplification of these beneficial antibodies by targeted DNA vaccines provided protective immunity in experimental models2-9. Interestingly, to date, no evidence correlating generation of autoimmunity to chemokines and cancer diseases exists.
Primary tumor growth, invasion and metastasis to distant organs are dependent on a highly orchestrated series of events. These events include cellular transformation, establishment of a pro-angiogenic environment, local tumor cell growth, invasion through the extracellular matrix (ECM) and vascular basement membrane and entry into the circulation, and finally, a nonrandom tumor-cell homing and metastasis to distant organs. It has been suggested that chemokines that direct leukocyte migration to target organs are also involved in tumor invasion10-12, angiogenesis13-15 and survival16. However, the significance of their role in the dynamics of tumor biology is still unclear.
MCP-1 (Monocyte chemoatractant protein-1, CCL2) is a CC chemokine which functions in attracting monocytes to a target tissue via chemotaxis; at the site of inflammation, MCP-1 further functions in activating monocytes to mature into macrophages17. Various cell types including monocytes, fibroblasts, endothelium, smooth muscle cells, and keratinocytes produce MCP-117. In addition to monocytes, MCP-1 can also attract T lymphocytes, neutrophils and NK cells, all of which express the CCR2 receptor. It is well established that MCP-1 plays a pivotal role in autoimmunity8,9,18-21. Specifically, the present inventors have previously shown that during T cell mediated autoimmune diseases, the immune system generates a beneficial autoimmune response to MCP-1 and that amplification thereof rapidly suppresses these diseases8,9.
Several recent studies have shown that some growth factors, cytokines and chemokines participate in prostate cancer tumor development24-29. Nevertheless, the role of MCP-1 in the regulation of prostate cancer has never been investigated or suggested.
While reducing the present invention to practice, the present inventor uncovered elevated levels of MCP-1 and autoantibodies thereagainst in prostate cancer patients and showed that antibodies which are directed at MCP-1 or a receptor thereof can prevent prostate cancer onset and metastasis. Thus, compositions and methods containing such agents can be utilized for diagnosing and treating prostate cancer.